Treatment of CNS disorders with trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine

ABSTRACT

Treatment of CNS disorders with (1R,4S)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine; and (1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is disclosed. A process for preparing 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine is also disclosed. The process includes the preparation of all four isomers of N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide, which are also useful.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 12/847,270 filed on Jul. 30, 2010, now U.S. Pat. No. 8,134,029,which is a continuation application of U.S. application Ser. No.12/538,583 filed on Aug. 10, 2009, now U.S. Pat. No. 7,790,772, which isa continuation of U.S. application Ser. No. 12/173,626, filed on Jul.15, 2008, now U.S. Pat. No. 7,589,237 which is a continuation of U.S.application Ser. No. 11/416,586, filed on May 3, 2006, now U.S. Pat. No.7,423,179 which is a continuation of U.S. application Ser. No.11/338,191, filed on Jan. 24, 2006, now abandoned which is acontinuation of U.S. application Ser. No. 11/220,891, filed on Sep. 7,2005, now U.S. Pat. No. 7,105,699, which is a continuation of U.S.application Ser. No. 10/663,173, filed on Sep. 16, 2003, now U.S. Pat.No. 7,087,785, and claims the priority of provisional applications60/411,304 and 60/411,305, both filed Sep. 16, 2002. The entiredisclosures of all of the prior applications and patents areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to methods of treating central nervoussystem (CNS) disorders using (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine;(1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamineand the four isomers ofN-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide.

BACKGROUND OF THE INVENTION

Clinicians recognize a distinction among central nervous systemillnesses, and there have been many schemes for categorizing mentaldisorders. The Diagnostic and Statistical Manual of Mental Disorders,Fourth Ed., Text Revision, (hereinafter, the “DSM-IV-TR™”), published bythe American Psychiatric Association, and incorporated herein byreference, provides a standard diagnostic system upon which persons ofskill rely. According to the framework of the DSM-IV-TR™, the CNSdisorders of Axis I include: disorders diagnosed in childhood (such as,for example, attention deficit disorder or “ADD” and attentiondeficit/hyperactivity disorder or “ADHD”) and disorders diagnosed inadulthood. CNS disorders diagnosed in adulthood include (1)schizophrenia and psychotic disorders; (2) cognitive disorders; (3) mooddisorders; (4) anxiety related disorders; (5) eating disorders; (6)substance related disorders; (7) personality disorders; and (8)“disorders not yet included” in the scheme.

Of particular interest to the present invention are adulthood disordersof DSM-IV-TR™ categories (1) through (7) and sexual disorders, currentlyclassified in category (8). Mood disorders of particular interestinclude depression, seasonal affective disorder and bipolar disorder.Anxiety related disorders of particular interest are agoraphobia,generalized anxiety disorder, phobic anxiety, obsessive compulsivedisorder (OCD), panic disorder, acute stress disorder, posttraumaticstress disorder, premenstrual syndrome, social phobia, chronic fatiguedisorder, perimenopause, menopause and male menopause.

In general, treatment for psychoses, such as schizophrenia, for example,is quite different than treatment for mood disorders. While psychosesare treated with D₂ antagonists such as olanzapine (the “typical” and“atypical” antipsychotics), mood disorders are treated with drugs thatinhibit the neuronal reuptake of monoamines, in particular, serotonin(5-HT), norepinephrine (NE) and dopamine (DA).

Common therapeutic agents for mood disorders include, but are notlimited to, selective serotonin reuptake inhibitors (SSRI's), includingfluoxetine, citalopram, nefazodone, fluvoxamine, paroxetine, andsertraline.

Sertraline, whose chemical name (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine, isapproved for the treatment of depression by the United States Food andDrug Administration, and is available under the trade name ZOLOFT®(Pfizer Inc., NY, N.Y., USA). In the human subject, sertraline has beenshown to be metabolized to (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, also knownas desmethylsertraline or norsertraline. Desmethylsertraline has beendescribed as “not contributing significantly to the serotonergic actionof sertraline” Ronfield et al., Clinical Pharmacokinetcs, 32:22-30(1997). Reports from Hamelin et al., Clinical Pharmacology &Therapeutics, 60:512 (1996) and Serebruany et al., PharmacologicalResearch, 43:453-461 (2001), have stated that norsertraline is“neurologically inactive”. These statements appear to be based onresults observed in serotonin-induced syndrome and ptosis in mousemodels in vivo, whereas the original Pfizer research papers suggested onthe basis of data in vitro that desmethylsertraline was a selectiveserotonin uptake inhibitor. Koe et al., JPET, 226:686-700 (1983).Sanchez et al., Cellular and Molecular Neurobiology, 19: 467 (1999),speculated that despite its lower potency, desmethylsertraline mightplay a role in the therapeutic effects of sertraline but, there ispresently no evidence in the literature to support this theory.

The primary clinical use of sertraline is in the treatment ofdepression. In addition, U.S. Pat. No. 4,981,870 discloses and claimsthe use of sertraline and norsertraline, as well as (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine and(1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine forthe treatment of psychoses, psoriasis, rheumatoid arthritis andinflammation. The receptor pharmacology of the individual (1S,4R) and(1R,4S) enantiomers of trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-napthalenamine isdescribed by Welch et al., J. Med. Chem., 27:1508-1515 (1984).

SUMMARY OF THE INVENTION

It has now been discovered that (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine (P) and(1S,4R)-trans 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine(Q) are useful in the treatment of CNS-related disorders that aremodulated by monoamine activity, and produce diminished side effects ascompared to the current standards of treatment. Treatable CNS disordersinclude, but are not limited to, mood disorders (e.g., depression),anxiety disorders (e.g., OCD), behavioral disorders (e.g., ADD andADHD), eating disorders, substance abuse disorders and sexual functiondisorders. The compounds are also useful for the prophylaxis ofmigraine.

Compounds P and Q are represented by the formulae:

In one aspect, the present invention relates to a method for treatingCNS disorders, which involves the administration of a therapeuticallyeffective amount of P or Q, or a pharmaceutically acceptable salt ofeither.

In another aspect, the invention relates totrans-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine of theformula (PQ):

In another aspect, the invention relates to a process for preparing4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine, whichinvolves:

-   -   (a) reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone        with an excess of formic acid and formamide to provide        N-[4-(3,4-dichloro        phenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide; and    -   (b) hydrolyzing the N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro        naphthalen-1-yl]formamide with aqueous acid, and thereby        yielding        4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides several embodiments of a method fortreating one or more CNS disorders. The method encompasses administeringpure P or pure Q, or any mixture thereof. Administration of eithercompound or any combination thereof, including the racemic mixture oftrans isomers, results in a broad therapeutic profile and avoidance ofside effects that are associated with an imbalance among thedistribution of activity between norepinephrine, serotonin and dopaminereceptors.

Preparation of compounds of the present invention is illustrated belowin Scheme 1 and its accompanying narrative.

In the compound

of Scheme 1, R is

wherein R′, R² and R³ are each independently alkyl. In a preferredembodiment of the compounds, R is tert-butyl.

N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide,the intermediate in the synthesis shown in Scheme 1, exists in fourstereoisomeric forms:

WhenN-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide issynthesized from achiral starting materials via non-stereoselectivesyntheses, all four isomers will be produced. The mixture can be readilyseparated into a racemic cis diastereomer and a racemic transdiastereomer by means, such as recrystallization or chromatography onachiral media, that rely on chemical and physical differences.

The trans diastereomer, represented as E below, is a 1:1 mixture of Aand B. When E is hydrolyzed, PQ is produced; when A is hydrolyzed, P isproduced; when B is hydrolyzed, Q is produced. The cis diastereomer,represented as F below, is a 1:1 mix of C and D.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62:114-120 (1985): solid and broken wedges are used to denotethe absolute configuration of a chiral element; wavy lines indicatedisavowal of any stereochemical implication which the bond it representscould generate; solid and broken bold lines are geometric descriptorsindicating the relative configuration shown but not implying anyabsolute stereochemistry; and wedge outlines and dotted or broken linesdenote enantiomerically pure compounds of indeterminate absoluteconfiguration.

Thus, formula PQ above indicates any mixture of the individual isomers Pand Q, which share the trans relative configuration. Clearly, the mostconvenient mixture is the 1:1 racemate. When a single enantiomer is tobe employed, it is preferred that the mixture include greater than 90%of the desired enantiomer, more preferably greater than 95%, and mostpreferably, greater than 98%. The percentages refer to the opticalpurity of the single enantiomer.

According to the present invention a therapeutically effective amount ofN-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide,which may be a pure isomer or a mixture of any or all of A, B, C and D,may also be administered to a person in need of therapy.

Disorders treatable with the compounds of the present invention include,but are not limited to: depression, bipolar disorder, chronic fatiguedisorder, seasonal affective disorder, agoraphobia, generalized anxietydisorder, phobic anxiety, obsessive compulsive disorder (OCD), panicdisorder, acute stress disorder, social phobia, posttraumatic stressdisorder, premenstrual syndrome, menopause, perimenopause and malemenopause.

Depression, for example, is characterized by changes in mood, and byfeelings of intense sadness or pessimistic worry. Symptoms includeinsomnia, anorexia, CNS slowing, as well as a loss of drive, enthusiasm,and libido.

Studies have shown that an increase in body monoamine levels, especiallyan increase in the level of norepinephrine, appears to reduce thesymptoms associated with the aforementioned disorders. Thus, thecompounds of the present invention are believed to provide theirtherapeutic activity by simultaneously blocking the reuptake ofnorepinephrine, serotonin and dopamine.

In addition to their beneficial therapeutic effects, compounds of thepresent invention provide the additional benefit of avoiding one or moreof the adverse effects associated with conventional mood disordertreatments. Such side effects include, for example, insomnia, breastpain, weight gain, extrapyramidal symptoms, elevated serum prolactinlevels and sexual dysfunction (including decreased libido, ejaculatorydysfunction and anorgasmia).

The compounds of the present invention are also effective for treatingdisruptive behavior disorders, such as attention deficit disorder (ADD)and attention deficit disorder/hyperactivity (ADHD), which is inaccordance with its accepted meaning in the art, as provided in theDSM-IV-TR™. These disorders are defined as affecting one's behaviorresulting in inappropriate actions in learning and social situations.Although most commonly occurring during childhood, disruptive behaviordisorders may also occur in adulthood.

The term ADD, as used herein, includes both attention deficit disorderand attention deficit/hyperactivity disorder (ADHD), and is used inaccordance with its accepted meaning in the art, which is defined in theDSM-IV-TR™. Accordingly, as used herein, the term attention deficitdisorder includes ADHD: DSM-IV-TR™ categories 314.xx (which includes314.01, 314.00 and 314.9); conduct disorder: DSM-IV-TR™ categories312.xx (which includes 312.81, 312.82 and 312.89, as well as312.9—disruptive behavior disorder); and oppositional defiant disorder:DSM-IV-TR™ category 313.81. The skilled artisan will recognize thatthere are alternate nomenclatures, nosologies, and classificationsystems for pathological conditions and that these systems evolve withmedical scientific progress.

Methylphenidate (RITALIN®; Novartis Pharmaceuticals Corporation, EastHanover, N.J., USA) is typically the drug of choice for the treatmentand/or prevention of ADD. Tricyclic antidepressants (such as, forexample, imipramine), caffeine, dextroamphetamine, and otherpsychostimulants (such as, for example, pemoline) are less preferredalternatives to methylphenidate. Common side effects of methylphenidateinclude sleep disturbances, depression or sadness, headache,stomachache, suppression of appetite, elevated blood pressure, and, withlarge continuous doses, a reduction of growth. Accordingly, alternatemeans of treating or preventing attention deficit disorders would be ofgreat benefit. Due to their strong dopaminergic component, compounds ofthe present invention not only provide effective treatment of disruptivebehavior disorders, but also, avoid many of the adverse effectsassociated with conventional treatments.

The term “treating” when used in connection with the foregoing disordersmeans amelioration, prevention or relief from the symptoms and/oreffects associated with these disorders and includes the prophylacticadministration of a compound of formula P or Q, a mixture thereof, or apharmaceutically acceptable salt of either, to substantially diminishthe likelihood or seriousness of the condition.

Compounds of the present invention are also effective for treatingeating disorders. Eating disorders are defined as a disorder of one'sappetite or eating habits or of inappropriate somatotype visualization.Eating disorders include, but are not limited to, anorexia nervosa;bulimia nervosa, obesity and cachexia.

Compounds of the invention are also effective for treating cerebralfunction disorders. The term cerebral function disorder, as used herein,includes cerebral function disorders involving intellectual deficits,and may be exemplified by senile dementia, Alzheimer's type dementia,memory loss, amnesia/amnestic syndrome, epilepsy, disturbances ofconsciousness, coma, lowering of attention, speech disorders,Parkinson's disease and autism.

The compounds of formulae P and Q are also effective for treating sexualdysfunction in both males and females. Disorders of this type include,for example, erectile dysfunction and orgasmic dysfunction related toclitoral disturbances.

Compounds of the present invention are also useful in the treatment ofsubstance abuse, including for example addiction to cocaine, heroin,nicotine, alcohol, anxiolytic and hypnotic drugs, cannabis (marijuana),amphetamines, hallucinogens, phenylcyclidine, volatile solvents, andvolatile nitrites. Nicotine addiction includes nicotine addiction of allknown forms, such as, for example, nicotine addiction resulting fromcigarette, cigar and/or pipe smoking, as well as addiction resultingfrom tobacco chewing. In this respect, due to their activity asnorepinephrine and dopamine uptake inhibitors, the compounds of thepresent invention function in a manner similar to that of buproprion(ZYBAN®, GlaxoSmithKline, Research Triangle Park, N.C., USA), byreducing the craving for the nicotine stimulus. As a benefit beyond thetherapeutic activity of buproprion, however, the compounds of thepresent invention provide an additional serotonergic component.

Compounds of the present invention are also effective in the prophylaxisof migraine.

The magnitude of a prophylactic or therapeutic dose of a compound offormula A-F, P or Q will vary with the nature and severity of thecondition to be treated and the route of administration. The dose, andperhaps the dose frequency, will also vary according to the age, bodyweight and response of the individual patient. In general, the totaldaily dose ranges of compounds of the present invention will be fromabout 25 mg per day to about 1000 mg per day, preferably about 100 mgper day to about 600 mg per day, in single or divided doses.

It is further recommended that children, patients over 65 years old, andthose with impaired renal or hepatic function, initially receive lowdoses and that the dosage be titrated based on individual responses andblood levels. It may be necessary to use dosages outside these ranges insome cases, as will be apparent to those in the art. Further, it isnoted that the clinician or treating physician knows how and when tointerrupt, adjust or terminate therapy in conjunction with individualpatient's response.

Any suitable route of administration may be employed. For example, oral,rectal, intranasal, and parenteral (including subcutaneous,intramuscular, and intravenous) routes may be employed. Dosage forms caninclude tablets, troches, dispersions, suspensions, solutions, capsulesand patches.

Pharmaceutical compositions of the present invention include as activeingredient, a single compound, or a mixture of compounds, of formulaA-F, P or Q, or a pharmaceutically acceptable salt of P or Q, togetherwith a pharmaceutically acceptable carrier and, optionally, with othertherapeutic ingredients.

The term “pharmaceutically acceptable salt thereof” refers to saltsprepared from pharmaceutically acceptable non-toxic acids includinginorganic acids and organic acids. Exemplary acids that formpharmaceutically acceptable salts with the amines of the invention, andthat may be used in the compositions of the present invention are aceticacid, benzenesulfonic (besylate) acid, benzoic acid, isethionic acid,camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid,gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid,lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonicacid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoricacid, succinic acid, sulfuric acid, p-toluenesulfonic acid and tartaricacid. The hydrochloric acid salt is particularly preferred.

Compositions suitable for oral, rectal, and parenteral administrationare encompassed by the present invention. A preferred route ofadministration is oral. The compositions may be conveniently presentedin unit dosage form and prepared by any of the methods well known in theart of pharmacy. Preferred unit dosage formulations are those containinga therapeutically effective dose, or an appropriate fraction thereof, ofthe active ingredient(s).

The compositions of the present invention will also include apharmaceutically acceptable carrier. The carrier may take a wide varietyof forms, depending on the route desired for administration, forexample, oral or parenteral (including intravenous). In preparing thecomposition for oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, water, glycols, oils, alcohols, flavoringagents, preservatives, and coloring agents in the case of oral liquidpreparation, including suspension, elixirs and solutions. Carriers suchas starches, sugars, microcrystalline cellulose, diluents, granulatingagents, lubricants, binders and disintegrating agents may be used in thecase of oral solid preparations such as powders, capsules and caplets,with the solid oral preparation being preferred over the liquidpreparations. Preferred solid oral preparations are tablets or capsules,because of their ease of administration. If desired, tablets may becoated by a standard aqueous or nonaqueous techniques. Oral andparenteral sustained release dosage forms may also be used.

Oral syrups, as well as other oral liquid formulations, are well knownto those skilled in the art, and general methods for preparing them arefound in any standard pharmacy school textbook, for example Remington:The Science and Practice of Pharmacy. Chapter 86 of the 19th edition ofRemington entitled “Solutions, Emulsions, Suspensions and Extracts”describes in complete detail the preparation of syrups (pages 1503-1505)and other oral liquids.

Similarly, sustained release formulation is well known in the art, andChapter 94 of the same reference, entitled “Sustained-Release DrugDelivery Systems,” describes the more common types of oral andparenteral sustained-release dosage forms (pages 1660-1675.) Therelevant disclosure of each of these chapters is incorporated herein byreference. Because they reduce peak plasma concentrations, as comparedto conventional oral dosage forms, controlled release dosage forms areparticularly useful for providing therapeutic plasma concentrationswhile avoiding the side effects associated with high peak plasmaconcentrations that occur with conventional dosage forms.

Synthesis of 2-methyl-propane-2-sulfinic acid[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-y-yl]-amide(tetralonet-butanesulfinimine): To a solution of4-((3,4-dicholorophenyl)-3,4-dihydro-1-naphthalenone (12 g) in THF (40mL) was added (R)-t-butanesulfinamide (5.2 g) and Ti(OEt)₄ (85 mL 20%)in EtOH. The reaction mixture was heated to 60° C. for 13 h. Thereaction mixture was cooled to rt, and poured into a brine solution (100mL) with stirring. The suspension was then added to EtOAc (300 mL) andstirred for 10 min. The suspension was filtered and the filtrate wasconcentrated to ca 50 mL. One hundred milliliters of EtOAc was added andthe organic phase was separated and concentrated to give a crudereaction mixture. The final products were isolated from the crudeproducts by careful flash column chromatography using EtOAc and hexane(3:7 to 1:1) to give ca 3 g starting ketone, and(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenonetert-butanesulfinimine (2.5 g, first product) as an oil that solidifiedon standing. ¹H NMR (CDCl₃) δ 1.33 (S, 9H), 2.10-2.20 (m, 1H), 2.28-2.38(m, 1H) 2.88-2.98 (m, 1H), 3.34-3.44 (m 1H), 4.12-4.24 (m, 1H),6.84-6.88 (m, 2H), 7.20 (s, 1H), 7.25-7.40 (m, 3H), 8.22-8.28 (m, 1H).The other product (1R,4R)-4-(3,4-dichlorophenyl)-3-4-dihydro-1-naphthalenone tert-butanesulfinimine (3.0 g,second product, lower R_(f)) was isolated also as an oil that solidifiedon standing. ¹H NMR (CDCl₃) δ 1.34 (S, 9H), 2.05-2.18 (m, 1H), 2.28-2.38(m, 1H), 3.15-3.25 (m, 2H), 4.16-4.22(m,1H),6.84-6.88(m,2H),7.20(s,1H),7.25-7.40(m,3H),8.22-8.28(m, 1H).

Synthesis of (R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone:(1R,4R)-4-(3,4-dichlorophenyl)3,4-dihydro-1-naphthalenonet-butanesulfinimine (3.0 g, second product) was dissolved in MeOH (20mL) and concentrated HCl (4 mL) at rt. The reaction mixture was stirredat rt to give a suspension. It was filtered and the solids were washedwith hexane to give 1.2 g product. The enantiomeric purity wasdetermined to be >99.3% by HPLC analysis with a ChiralPak AS 10 μm,4.6×250 mm, Hexane/IPA (90:10), UV 220 nm, R-isomer 8.23 min. S-isomer12.25 min. ¹H NMR (CDCl₃) δ 2.20-2.32 (m, 1H), 2.42-2.53 (m, 1H)2.57-2.78 (m,2H), 4.28 (dd=4.6, 8.1 Hz, 1H), 6.95 (dd, J=2.1, 7.6 Hz,2H), 7.23 (d J=2.0 Hz, 1H), 7.37-50 (m, 3H), 8.13 (d, J=7.6 Hz, 1H).[α]=−66° (c=1, acetone).

Synthesis of (S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone Theprevious procedure was used, starting from(1R,4S)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenonetert-butanesulfinimine. 1.7 g of product (>99% ee) was obtained. [α]=+62(c=1, acetone). ¹H NMR spectrum of the product is the same as that ofits enantiomer.

Synthesis of (1S,4R) and(1R,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-formamide:(R)-4-(3,4-dichlorophenyl)-3,4-dihydro-1-naphthalenone (1.2 g) was addedformic acid (3 mL) and formamide (3 mL). The reaction mixture was heatedto 160-165° C. for 15 h under nitrogen atmosphere. The reaction mixturewas cooled to rt and decanted the solvent. The residue solids was passedthrough flash column using EtOAc:Hexane (3:7 to 1:1) to give the(1R,4R)-formamide (400 mg, first spot), and the (1S,4R)-formamide (360mg). ¹H NMR of the first product [(1R,4R)-isomer]: (CDCl₃) δ 1.80-2.10(m, 3H), 2.10-2.20 (m, 1H), 4.00-4.10 (m, 1H), 5.22-5.30 (m, 1H),6.10-6.20 (m, 1H), 6.80-6.90 (M, 1H), 6.90-6.96 (m, 1H), 7.10-7.40 (m,5H), 8.22 (s, 1H). M+320. ¹H NMR of the second product [(1S,4R)-isomer:δ 1.64-1.90 (m, 2H), 2.10-2.28 (m, 2H), 4.10 (m, 1H), 5.38-5.42 (m, 1H),5.82-6.05 (m, 1H), 6.80-6.90 (m, 2H), 7.10-40 (m, 5H), 8.28 (s, 1H).Mass Spec. M⁺320.

Synthesis of (1S,4R)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: (1S,4R)formamide (ca 300 mg) was dissolved in MeOH (5 mL) followed by additionof 6N HCl (6 mL). The reaction mixture was heated to 80° C. for 2 h. Thereaction mixture was cooled to rt for 1 h and filtered to collect thesolid. It was washed with acetone (3 mL) and dried to give the product(280 mg). Enantiomeric purity was determined to be >99.8% by HPLCanalysis with a ChiralPak AD 10 μm, 4.6×250 mm, Hexane/IPA/DEA(99:1:0.1), UV 220 nm, (1R,4S)-isomer, 11.00 min. (1S,4R)-isomer 11.70min [α]=−51° (C=1, MeOH). ¹H NMR (CD₃OD) δ 1.86-1.97 (m, 2H), 2.20-2.42(m, 2H), 4.30 (broad s, 1H), 4.67 (broad s, 1H), 4.87 (s, 3H), 6.95-6.99(m, 2H), 7.18 (s, 1H), 7.28-7.50 (m, m, 4H). M⁺293.

Synthesis of (1R,4S)-trans4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It wasobtained similarly from (1R,4S) formamide with HCl hydrolysis. Ee of theproduct is >99.8% based on HPLC analysis with a ChiralPak AD 10 μm,4.6×250 mm, Hexane/IPA/DEA (99:1:0.1), UV 220 nm, (1R,4S)-isomer 11.00min. (1S,4R)-isomer 11.70 min.

Synthesis of (1R,4R)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It wasobtained similarly from (1R,4R) formamide with HCl hydrolysis.Enantiomeric purity was determined to be 96.8% by HPLC analysis with aChiralPak AD 10 μm, 4.6×250 mm, Hexane/IPA/DES (99:1:0.1), UV 220 nm,(1R,4R)-isomer 11.84 min. (1S,4S)-isomer 9.80 min. ¹H NMR (CD₃OD) δ1.96-2.26 (m, 4H), 4.14-4.22 (m, 1H), 4.54-4.63 (m, 1H), 4.87 (s, 3H),7.88-7.94 (m, 1H), 7.18-7.20 (m, 1H), 7.30-7.50 (m, 5H). Mass SpecM⁺292.

Synthesis of (1S,4S)-cis4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine HCl: It wasobtained similarly from (1S,4S) formamide. Ee of the product was 98.5%by HPLC analysis. ¹H NMR spectrum is the same as the enantiomer. MassSpec M⁺292.

The compounds of the invention were tested for their inhibition offunctional uptake of serotonin (5-HT), norepinephrine (NE), or dopamine(DA), in synaptosomes prepared from rat whole brain, hypothalamus, orcorpus striatum, respectively. Compounds were tested initially at 10 μMin duplicate, and if ≧50% inhibition of uptake was observed, they weretested further at 10 different concentrations in duplicate in order toobtain full inhibition curves. IC₅₀ values (concentration inhibitingcontrol activity by 50%) were then determined by nonlinear regressionanalysis of the inhibition curves and tabulated below.

Experimental Conditions for Monoamine Uptake Assays

Serotonin Functional Uptake Assay

Characterization of serotonin uptake is performed using synaptosomesisolated in a 0.32M sucrose buffer from a male Wistar rat cortex. Theuptake of radiolabelled serotonin by synaptosomes (100 μg ofproteins/point) is allowed by incubating them in a deep well for 15 minat 37° C. in presence of test compounds and [³H]5-hydroxytryptamine (0.1μCi/point).

Synaptosomes and [³H]5-hydroxytryptamine are prepared in a Krebs bufferpH 7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid.This incubation buffer is oxygenated during 5 minutes before incubation.Basal control is incubated for 15 minutes at 4° C. in order to avoid anyuptake. Following this incubation the uptake is stopped by filtrationthrough an “unifilter 96-wells GFB Packard plate” washed with Krebsbuffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]5-hydroxytryptamine. The radioactivity associated to thesynaptosomes retained onto the unifilter corresponding to the uptake isthen measured with a microplate scintillation counter Topcount, Packardusing a scintillation liquid microscint 0, Packard.

The reference compound is imipramine tested at 10 concentrations rangingfrom 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See, Perovicsand Müller, “Pharmacological profile of hypericum extract: effect onserotonin uptake by postsynaptic receptors,” Arzeim. Forsch./Drug Res.,45:1145-1148 (1995).

Dopamine Functional Uptake Assay

Characterization of dopamine uptake is performed using synaptosomesisolated at Cerep in a 0.32 M sucrose buffer from a male Wistar ratstriatum. The uptake of radiolabelled dopamine by synaptosomes (20 μg ofproteins/point) is allowed by incubating them for 15 minutes at 37° C.in presence of test compounds and [³H]-dopamine (0.1 μCi/point). Theexperiment is performed in a deep well. Synaptosomes and [³H]-dopamineare prepared in a Krebs buffer pH 7.4 containing 25 mM NaHCO₃, 11 mMglucose and 50 μM ascorbic acid. This incubation buffer is oxygenatedduring 5 minutes before incubation. Basal control is incubated for 15minutes at 4° C. in order to avoid any uptake. Following this incubationthe uptake is stopped by filtration through an “unifilter 96-wells GFBPackard plate” washed with Krebs buffer containing 25 mM NaHCO₃ in orderto eliminate free [³H]-dopamine. The radioactivity associated to thesynaptosomes retained onto the unifilter corresponding to the uptake isthen measured with a microplate scintillation counter Topcount, Packardusing a scintillation liquid microscint 0, Packard. The referencecompound is GRB 12909 tested at 8 concentrations ranging from 10⁻¹¹ M to10⁻⁶M in order to obtain an IC₅₀ value. See, Jankowsky et al.,“Characterization of sodium-dependent [³H]GBR-12935 binding in brain: aradioligand for selective labeling of the dopamine transport complex,” JNeurochem, 46:1272-1276 (1986).

Norepinephrine Functional Uptake Assay

Characterization of norepinephrine uptake is performed usingsynaptosomes isolated at Cerep in a 0.32 M sucrose buffer from a maleWistar rat hypothalamus. The uptake of radiolabeled norepinephrine bysynaptosomes (100 μg of proteins/point) is allowed by incubating themfor 20 minutes at 37° C. in presence of test compounds and[³H]-norepinephrine (0.1 μCi/point). The experiment is performed in adeep well.

Synaptosomes and [³H]-norepinephrine are prepared in a Krebs buffer pH7.4 containing 25 mM NaHCO₃, 11 mM glucose and 50 μM ascorbic acid. Thisincubation buffer is oxygenated during 5 minutes before incubation.Basal control is incubated for 20 minutes at 4° C. in order to avoid anyuptake. Following this incubation the uptake is stopped by filtrationthrough an “unifilter 96-wells GFB “Packard plate washed with Krebsbuffer containing 25 mM NaHCO₃ in order to eliminate the free[³H]-norepinephrine. The radioactivity associated to the synaptosomesretained onto the unifilter corresponding to the uptake is then measuredwith a microplate scintillation counter Topcount, Packard using ascintillation liquid microscint 0, Packard.

The reference compound is imipramine tested at 13 concentrations rangingfrom 10⁻¹¹ M to 10⁻⁵ M in order to obtain an IC₅₀ value. See, Perovicsand Müller, “Pharmacological profile of hypericum extract: effect onserotonin uptake by postsynaptic receptors,” Arzeim. Forsch./Drug Res.,45:1145-1148 (1995). The results of the monoamine uptake assays areprovided in Table 1.

TABLE 1 IC₅₀ Values (μM) for Compounds of the Invention in FunctionalMonoamine Uptake Assays 5-HT NE DA sertraline 0.0016 0.31 0.048 P 0.00770.0096 0.0064 Q 0.088 0.035 0.019 P + Q 0.041 0.0088 0.0071 imipramine(standard) 0.054/0.051 — — protriptyline (standard) — 0.0036 — GBR 12909(standard) — — 0.0028/0.0051/0.0034 / separates multiple determinations— <50% inhibition

As shown in Table 1, P and Q exhibit similar inhibitory potency on theneuronal uptake of NE, DA, and 5HT. Currently, the therapeutic approachto treating affective disorders in man is the selective inhibition of asingle monoamine uptake mechanism or the dual inhibition of two of thesemolecular targets. The equipotent inhibition of the neuronal uptake ofNE, DA and 5HT provides the clinician with the ability to moreeffectively treat affective disorders and eating disorders by elevatingall of the monoamine levels in the brain simultaneously and over thesame dose-range without the need to titrate separate drugs. For thoseCNS disorders that are presently treated with dopaminergic,norepinephrine or mixed DA-NE uptake inhibitors (e.g. OCD, ADD, ADHD,sexual dysfunction and substance abuse), the equipotent inhibition ofthe neuronal uptake of NE, DA and 5HT provides more effective treatmentby adding the serotonergic effect.

The results of the monoamine uptake assays for compounds A-F areprovided in Table 3.

TABLE 3 IC₅₀ Values (μM) for Formamides A-F in Functional MonoamineUptake Assays N-[4-(3,4- dichlorophenyl)-1,2,3,4- tetrahydronaphthalen-1-yl]formamide 5-HT NE DA (R,S/S,R) trans = E = 7.5 0.40 0.51 A + B(R,R/S,S) cis = F = — 3.9 0.53 C + D bupropion 0.611 0.294 (positivecontrol) sertraline 0.0016 0.31 0.048 (positive control) Impiramine(standard) 0.054/0.051 Protriptyline (standard) 0.0036 GBR 12909(standard) 0.0028/0.0051/0.0034 / separates multiple determinationsempty cell indicates <50% inhibition

As shown in Table 3, the diastereomeric cis and transN-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamideexhibit therapeutically useful inhibitory potency on neuronal uptake ofdopamine. The trans diastereomer also exhibits a reasonable inhibitorypotency on neuronal uptake of norepinephrine.

TABLE 4 Effect of Intraperitoneal Administration of (R,S/S,R) N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl]formamide (E) inthe Behavioral Despair Test in Mice (N = 10) Imipramine Compound Vehicle10 mg/kg E 10 mg/kg E 50 mg/kg Immobility 188 64 50 0 Duration 183 28 5915 (sec.) 167 156 162 0 199 98 131 98 174 0 22 34 158 0 167 59 124 63 5825 157 30 135 63 179 56 122 0 222 116 164 15 Mean 175 61 107 31 ±sem 816 10 Dunnett P < 0.05 * * * Vehicle = 1% methylcellulose * indicates asignificant difference vs vehicle for P < 0.05 (Dunnett test)

Exemplary pharmaceutical formulations of the present invention include:

Tablets - Composition per unit dosage P 25 mg Croscarmellose 60 mgcolloidal silicon dioxide  8 mg magnesium stearate  1 mgmicrocrystalline cellulose 190 mg  Croscarmellose 15 mg Talc 10 mg Total534 mg 

The P (or other compound of the invention) and silicon dioxide are drymixed, the first portion of croscarmellose is added and the mixture isfurther dry mixed. The magnesium stearate is added, dry mixed and themixture is run through a roller compactor and mill. The resulting drygranulate is mixed with the remaining three ingredients and compressedinto tablets.

Powder-filled Capsules - Composition per unit dosage P 200 mg Lactose250 mg Corn starch  60 mg magnesium stearate  5 mg Total 515 mg

The P, lactose and cornstarch, in the proportions shown above, areblended until uniform and then the magnesium stearate is blended intothe resulting powder, which is sieved and filled into suitably sized,two-piece, hard gelatin capsules using conventional machinery. Otherdoses may be prepared by altering the fill weight and, if necessary,changing the capsule size to suit.

Pharmaceutical formulations of the formamides A-F may be prepared insimilar fashion.

1. A method for treating a cognitive disorder, the method comprisingadministering to a person in need of treatment for a cognitive disordera therapeutically effective amount of a compound of formula PQ:

or a salt thereof.
 2. A method according to claim 1, wherein thecompound of formula PQ is selected from formula P or Q:

or a salt thereof.
 3. A method according to claim 1, wherein thecompound of formula PQ is(1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamineor a salt thereof.
 4. A method according to claim 1, wherein thecompound of formula PQ is(1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamineor a salt thereof.
 5. A method according to claim 1, wherein thecompound of formula PQ is(1S,4R)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenaminehydrochloride.
 6. A method according to claim 1, wherein the compound offormula PQ is(1R,4S)-N-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenaminehydrochloride.